Abstract
Cancer is a complex pathology of great heterogeneity and difficulty that makes the constant search for new therapies necessary. A major advance on the subject has been made by focusing on the development of new drugs aimed to alter the metabolism of cancer cells, by generating a disruption of mitochondrial function. For this purpose, several new compounds with specific mitochondrial action have been tested, leading successfully to cell death. Recently, attention has centered on a group of natural compounds present in plants named polyphenols, among which is caffeic acid, a polyphenol that has proven to be a powerful antitumoral agent and a prominent compound for studies focused on the development of new therapies against cancer.
In this review, we revised the antitumoral capacity and mechanisms of action of caffeic acid and its derivatives, with special emphasis in a new class of caffeic acid derivatives that target mitochondria by chemical binding to the lipophilic cation triphenylphosphonium.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- α-KG:
-
Alpha-ketoglutarate
- ΔΨp:
-
Plasma membrane potential
- ΔΨm:
-
Membrane potential of the MII
- 2-HG:
-
2-Hydroxyglutarate
- AMPK:
-
AMP-activated protein kinase
- CA:
-
Caffeic acid
- CAPE:
-
Caffeic acid phenethyl ester
- CAPPE:
-
Caffeic acid phenylpropyl ester
- Cyt c:
-
Cytochrome c
- DR5:
-
Death receptor 5
- DRP-1:
-
Dynamin-related protein 1
- ETC:
-
Electron transport chain
- FDA:
-
Food and Drug Administration
- GSH-Px:
-
Glutathione peroxidase
- HIF:
-
Hypoxia-induced factor
- IMM:
-
Inner mitochondrial membrane
- IC50:
-
Inhibitory concentration 50
- MDIVI-1:
-
Mitochondrial division inhibitor 1
- MitoCaA:
-
Mitochondriotropic caffeic acid
- MitoCA:
-
Mitochondriotropic cinnamic acid
- MitoFA:
-
Mitochondriotropic ferulic acid
- Mitop-CoA:
-
Mitochondriotropic p-coumaric acid
- mIDH:
-
Mutant isocitrate dehydrogenase
- MMP:
-
Mitochondrial membrane potential
- MMP2:
-
Matrix metalloproteinase 2
- MMP9:
-
Matrix metalloproteinase 9
- mtDNA:
-
Mitochondrial DNA
- mtROS:
-
Mitochondrial ROS
- mTOR:
-
Mechanistic target of rapamycin
- NFκB:
-
Nuclear factor kappa B
- O2-:
-
Superoxide anion
- OH-:
-
Hydroxyl radical
- PI3-K/Akt:
-
Phosphoinositide 3-kinase/protein kinase B
- p38:
-
Mitogen-activated protein kinase
- ROS:
-
Reactive oxygen species
- SI:
-
Selectivity indexes
- SODs:
-
Superoxide dismutases
- TCA:
-
Tricarboxylic acid
- TRAIL:
-
Tumor necrosis factor-related apoptosis-inducing ligand
- TPP+:
-
Triphenylphosphonium
- VEGF:
-
Vascular endothelial growth factor
References
Abou Dalle I, DiNardo CD (2018, Jul) The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia. Ther Adv Hematol 9(7):163–173. https://doi.org/10.1177/2040620718777467
Anderson RG, Ghiraldeli LP, Pardee TS (2018a) Mitochondria in cancer metabolism, an organelle whose time has come? Biochim Biophys Acta Rev Cancer 1870(1):96–102. https://doi.org/10.1016/j.bbcan.2018.05.005. Elsevier B.V., Aug. 01, 2018
Anderson NM, Mucka P, Kern JG, Feng H (2018b) The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell 9(2):216–237. https://doi.org/10.1007/s13238-017-0451-1. Higher Education Press, Feb. 01, 2018
Ashton TM, Gillies McKenna W, Kunz-Schughart LA, Higgins GS (2018) Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res 24(11):2482–2490. https://doi.org/10.1158/1078-0432.CCR-17-3070. American Association for Cancer Research Inc., Jun. 01, 2018
***, “Caffeic acid | C9H8O4 – PubChem.” https://pubchem.ncbi.nlm.nih.gov/compound/689043#section=Pharmacology-and-Biochemistry. Accessed 29 July 2020
Chen L, Cui H (2015) Targeting glutamine induces apoptosis: a cancer therapy approach. Int J Mol Sci 16(9):22830–22855. https://doi.org/10.3390/ijms160922830. MDPI AG, Sep. 22, 2015
Chiang E-PI et al (2014, Jun) Caffeic acid derivatives inhibit the growth of colon cancer: involvement of the PI3-K/Akt and AMPK signaling pathways. PLoS One 9(6):e99631. https://doi.org/10.1371/journal.pone.0099631
Comité Nacional de Estadísticas Vitales (2017) ANUARIO DE ESTADÍSTICAS VITALES, 2017 Período de información : 2017. Anu. Estad. Vitales
Damasceno SS, Dantas BB, Ribeiro-Filho J, Antônio D, Araújo M, da Costa JGM (2017) Chemical properties of caffeic and ferulic acids in biological system: implications in cancer therapy. A review. Curr Pharm Des 23(20):3015–3023. https://doi.org/10.2174/1381612822666161208145508
Dickerson T, Jauregui CE, Teng Y (2017) Friend or foe? Mitochondria as a pharmacological target in cancer treatment. Fut Med Chem 9(18):2197–2210. https://doi.org/10.4155/fmc-2017-0110. Future Medicine Ltd., Dec. 01, 2017
Dong Z et al (2019) Biological functions and molecular mechanisms of antibiotic tigecycline in the treatment of cancers. Int J Mol Sci 20(14). https://doi.org/10.3390/ijms20143577. MDPI AG, Jul. 02, 2019
Fiorillo M et al (2016, Jun) Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget 7(23):34084–34099. https://doi.org/10.18632/oncotarget.9122
Fitzmaurice C et al (2019, Dec) Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol 5(12):1749–1768. https://doi.org/10.1001/jamaoncol.2019.2996
Frattaruolo L, Brindisi M, Curcio R, Marra F, Dolce V, Cappello AR (2020) Targeting the mitochondrial metabolic network: a promising strategy in cancer treatment. Int J Mol Sci 21(17):1–21. https://doi.org/10.3390/ijms21176014. MDPI AG, Sep. 01, 2020
Grasso D, Zampieri LX, Capelôa T, Van De Velde JA, Sonveaux P (2020) Mitochondria in cancer. Cell Stress 4(6):114–146. https://doi.org/10.15698/cst2020.06.221. Isfahan University of Medical Sciences (IUMS), Jun. 01, 2020
Idelchik M d PS, Begley U, Begley TJ, Melendez JA (2017, Dec) Mitochondrial ROS control of cancer. Semin Cancer Biol 47:57–66. https://doi.org/10.1016/j.semcancer.2017.04.005
Kabała-Dzik A, Rzepecka-Stojko A, Kubina R, Wojtyczka RD, Buszman E, Stojko J (2018, Dec) Caffeic acid versus caffeic acid phenethyl ester in the treatment of breast cancer MCF-7 cells: migration rate inhibition. Integr Cancer Ther 17(4):1247–1259. https://doi.org/10.1177/1534735418801521
Kalyanaraman B et al (2018) A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: therapeutic targeting of tumor mitochondria with lipophilic cationic compounds. Redox Biol 14:316–327. https://doi.org/10.1016/j.redox.2017.09.020. Elsevier B.V., Apr. 01, 2018
Konteatis Z et al (2020, Feb) Vorasidenib (AG-881): a first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma. ACS Med Chem Lett 11(2):101–107. https://doi.org/10.1021/acsmedchemlett.9b00509
Li J et al (2017, Jan) Synthesis of hydroxycinnamic acid derivatives as mitochondria-targeted antioxidants and cytotoxic agents. Acta Pharm Sin B 7(1):106–115. https://doi.org/10.1016/j.apsb.2016.05.002
Mazumder S et al (2019, May) Indomethacin impairs mitochondrial dynamics by activating the PKCζ-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells. J Biol Chem 294(20):8238–8258. https://doi.org/10.1074/jbc.RA118.004415
Modica-Napolitano JS, Weissig V (2015) Treatment strategies that enhance the efficacy and selectivity of mitochondria-targeted anticancer agents. Int J Mol Sci 16(8):17394–17421. https://doi.org/10.3390/ijms160817394. MDPI AG, Jul. 29, 2015
Monteiro Espíndola KM et al (2019) Chemical and pharmacological aspects of caffeic acid and its activity in hepatocarcinoma. Front Oncol 9(JUN):541. https://doi.org/10.3389/fonc.2019.00541. Frontiers Media S.A., 2019
Popovici-Muller J et al (2018, Apr) Discovery of AG-120 (Ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett 9(4):300–305. https://doi.org/10.1021/acsmedchemlett.7b00421
Prasetyanti PR, Medema JP (2017) Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Canc 16(1):41. https://doi.org/10.1186/s12943-017-0600-4. BioMed Central Ltd., Feb. 16, 2017
Protasoni M, Kroon AM, Taanman JW (2018, Sep) Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3. Oncotarget 9(73):33818–33831. https://doi.org/10.18632/oncotarget.26107
Quiñones M, Miguel M, Aleixandre A (2012) Los polifenoles, compuestos de origen natural con efectos saludables sobre el sistema cardiovascular. Nutr Hosp organo Of la Soc Espa??ola Nutr Parenter y Enter 27(1):76–89. https://doi.org/10.3305/nh.2012.27.1.5418
Stuart SD et al (2014) A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab 2(1):4. https://doi.org/10.1186/2049-3002-2-4
Teixeira J et al (2017) Development of a mitochondriotropic antioxidant based on caffeic acid: proof of concept on cellular and mitochondrial oxidative stress models. J Med Chem 60(16):7084–7098. https://doi.org/10.1021/acs.jmedchem.7b00741
Teixeira J, Deus CM, Borges F, Oliveira PJ (2018) Mitochondria: targeting mitochondrial reactive oxygen species with mitochondriotropic polyphenolic-based antioxidants. Int J Biochem Cell Biol 97:98–103. https://doi.org/10.1016/j.biocel.2018.02.007. Elsevier Ltd, Apr. 01, 2018
Urra FA, Muñoz F, Lovy A, Cárdenas C (2017) The mitochondrial complex(I)ty of cancer. Front Oncol 7(JUN):118. https://doi.org/10.3389/fonc.2017.00118. Frontiers Media S.A., Jun. 08, 2017
Zhou Y et al (2016) Natural polyphenols for prevention and treatment of cancer. Nutrients 8(8). https://doi.org/10.3390/nu8080515. MDPI AG, Aug. 22, 2016
Zielonka J et al (2017) Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem Rev 117(15):10043–10120. https://doi.org/10.1021/acs.chemrev.7b00042. American Chemical Society, Aug. 09, 2017
Acknowledgments
This review was supported by Fondo Nacional de Ciencia e Investigación (FONDECYT) grant 11160281 (M.C.).
Supplementary Materials
Not applied.
Author Contributions
H.B., G.A.V., and M.C. wrote the manuscript. H.B. and G.A.V. did all the figures and table. G.A.V., G.C., J.A.J., and MC edited the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
Funding
This research received no external funding.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Bastidas, H., Araya-Valdés, G., Cortés, G., Jara, J.A., Catalán, M. (2022). Pharmacological Effects of Caffeic Acid and Its Derivatives in Cancer: New Targeted Compounds for the Mitochondria. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 17. Advances in Experimental Medicine and Biology(), vol 1401. Springer, Cham. https://doi.org/10.1007/5584_2022_718
Download citation
DOI: https://doi.org/10.1007/5584_2022_718
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-20513-2
Online ISBN: 978-3-031-20514-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)